The overall objective of the proposed research is to improve survival and palliation for patients with locally unresectable adenocarcinoma of the pancreas. Of all the patients diagnosed with adenocarcinoma of the pancreas, only about 10% are candidates for definitive surgery. Approximately half of the remaining patients are considered unresectable because of the local extent of disease rather than distant metastases. At present, almost all of these patients die of cancer. The proposed project addresses this group of patients with a combination of three treatment modalities that have previously shown promise in this disease: interstitial implantation of radioactive sources into the tumors, precision high dose (PHD) external beam radiotherapy, and 5-fluorouracil (5-FU) adjuvant chemotherapy. Forty-five patients with locally unresectable pancreatic carcinoma will be studied over the course of 3 years. Pre-treatment: The local and distant spread of disease will be studied extensively, as will the status of organs adjacent to the pancreas. Intraoperative interstitial implants of 125I will deliver local tumor doses of approximately 14,000 rad. PHD external beam radiation therapy from an 18 MV linear accelerator will deliver 6000 rad in 7 weeks to the tumor plus a margin of 1-2 cm. Subsequent adjuvant 5-FU will be given weekly intravenously in a dose of 500 mg/m2. Patients will be followed regularly and studied with regard to the local toxic effects of combined modality therapy. Local toxicity will be analyzed as a function of total combined radiation dose. Patient survival will be compared to that of patients treated by PHD therapy alone and to historical controls.